title: Dietary diacetylene falcarindiol induces phase 2 drug-metabolizing enzymes and blocks carbon tetrachloride-induced hepatotoxicity in mice through suppression of lipid peroxidation.
abstract: Falcarindiol is a diacetylenic natural product containing unique carbon-carbon triple bonds. Mice were orally administrated falcarindiol (100 mg/kg), and drug-metabolizing and antioxidant enzymes were monitored in several tissues of mice. Treatment with falcarindiol was found to increase glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 activities in liver, small intestine, kidney, and lung. No changes were observed in cytochrome P450 (CYP) 1A known to activate procarcinogens. Western blot analysis revealed that various GST subunits including GSTA4, which plays an important role in the detoxification of alkenals produced from lipid peroxides, were induced in liver, small intestine, and kidney of falcarindiol-treated mice. Additionally, we investigated the protective effects of falcarindiol against hepatotoxicity induced by carbon tetrachloride (CCl(4)) and the mechanism of its hepatoprotective effect. Pretreatment with falcarindiol prior to the administration of CCl(4) significantly suppressed both an increase in serum alanine transaminase/aspartate transaminase (ALT/AST) activity and an increase in hepatic thiobarbituric acid reactive substance levels without affecting CCl(4)-mediated degradation of CYP2E1. Formation of hexanoyl-lysine and 4-hydroxy-2(E)-nonenal-histidine adducts, lipid peroxidation biomarkers, in homogenates from the liver of CCl(4)-treated mice was decreased in the group of mice pretreated with falcarindiol. These results suggest that the protective effects of falcarindiol against CCl(4) toxicity might, in part, be explained by anti-lipid peroxidation activity associated with the induction of the GSTs including GSTA4.
authors.affiliation: Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192–0392, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ohnuma
authors.forename: Eisaburo
authors.initials: E
authors.lastname: Anan
authors.forename: Rika
authors.initials: R
authors.lastname: Hoashi
authors.forename: Yuika
authors.initials: Y
authors.lastname: Takeda
authors.forename: Takahito
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ogura
authors.forename: Akira
authors.initials: A
authors.lastname: Hiratsuka
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D019661:Apiaceae / Q000737:chemistry; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000517:prevention & control*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D053280:Diynes / Q000494:pharmacology / Q000627:therapeutic use*; D005233:Fatty Alcohols / Q000494:pharmacology / Q000627:therapeutic use*; D005982:Glutathione Transferase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D050217:Metabolic Detoxication, Phase II / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000975:Antioxidants; D053280:Diynes; D005233:Fatty Alcohols; D010936:Plant Extracts; D017392:Thiobarbituric Acid Reactive Substances; C034379:falcarindiol; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D009247:NADH, NADPH Oxidoreductases; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase